Process for production of glycopyrronium tosylate

ABSTRACT

Provided herein are methods for the production of glycopyrronium tosylate and glycopyrronium tosylate compositions. Also provided herein are compositions useful in the production of glycopyrronium tosylate. Additionally provided herein are glycopyrronium tosylate compositions. Glycopyrronium tosylate is useful for the treatment of, among other conditions, hyperhidrosis.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims benefit of, and priority to under 35 U.S.C. §119(e), U.S. Provisional Application Ser. No. 62/039,811, entitled“PROCESS FOR PRODUCTION OF GLYCOPYRRONIUM TOSYLATE,” filed on Aug. 20,2014, which is incorporated by reference herein in its entirety.

FIELD

Provided herein are methods for the production of glycopyrroniumtosylate. Also provided herein are compositions useful in the productionof glycopyrronium tosylate. Glycopyrronium tosylate is useful for thetreatment of, among other conditions, hyperhidrosis.

BACKGROUND

Glycopyrrolate is a salt of quaternary ammonium cation of the muscarinicanticholinergic group. Glycopyrrolate, typically as a bromide salt, hasbeen described for the treatment of a variety of conditions includingdiarrhea (U.S. Pat. Nos. 6,214,792 B1 and 5,919,760 A), urinaryincontinence (U.S. Pat. Nos. 6,204,285 B1 and 6,063,808 A), and anxiety(U.S. Pat. No. 5,525,347 A). Glycopyrrolate has also been described forthe treatment of hyperhidrosis in U.S. Pat. Appl. No. US 2010/0276329A1.

Glycopyrrolate has been made available as a bromide salt or an acetatesalt. The bromide salt of glycopyrrolate is sold as Rubinol®. The term“glycopyrrolate” as used in the label for Rubinol® refers to the bromidesalt, also more formally referred to as glycopyrronium bromide.Glycopyrronium tosylate has been described in U.S. Pat. No. 8,558,008B2. Glycopyrrolate used pharmaceutically is the racemic threo form.

Glycopyrronium bromide is commercially available and the synthesis hasbeen described in U.S. Pat. No. 2,956,062 and in Finnish Pat. No.49,713. Several routes for the production of glycopyrronium tosylatehave been described in U.S. Pat. No. 8,558,008 B2.

SUMMARY

Provided herein are methods of producing glycopyrronium tosylate useful,for example, for the treatment of hyperhidrosis. Also provided hereinare compositions useful in the preparation of glycopyrronium tosylate.

In certain embodiments, methods of producing glycopyrronium tosylatedescribed herein comprise the use of methyl tosylate as a methylatingagent. Prior methods for the production of glycopyrronium bromidedescribed the use of methylbromide as a methylating agent. See, FinnishPat. No. 49,713. Prior methods of production of glycopyrronium tosylatedescribed exchange of glycopyrronium acetate and p-toluenesulfonic acid,or exchange of glycopyrronium bromide and silver tosylate. See, U.S.Pat. No. 8,558,008 B2. The methods described herein provide a novelmethod to produce glycopyrronium tosylate by the use of methyl tosylateas a methylating agent. This novel method comprises fewer steps andresults in enhanced stereochemical selection with respect to priormethods to produce glycopyrronium tosylate. Furthermore, incompleteanion exchange and silver contamination associated with previouslydescribed methods are avoided. Avoidance of the use of expensive silversalts renders the large scale manufacture of glycopyrronium tosylateeconomically more viable and environmentally more sound using the methoddescribed herein.

In an aspect, provided herein are methods of producing glycopyrroniumtosylate comprising contacting glycopyrrolate base with methyl tosylateto produce glycopyrronium tosylate:

In an embodiment, provided herein are methods of producingglycopyrronium tosylate comprising:

(i) contacting cyclopentylmandelic acid with 1-methylpyrrolidin-3-ol toform glycopyrrolate base:

(ii) contacting the glycopyrrolate base with 5-nitroisophthalic acid toform glycopyrrolate base, 5-nitroisophthalate salt:

(iii) contacting the glycopyrrolate base, 5-nitroisophthalate salt withan inorganic base to form glycopyrrolate base:

and

(iv) contacting the glycopyrrolate base with methyl tosylate to produceglycopyrronium tosylate:

The glycopyrrolate base has two stereocenters, as indicated above. Assuch, provided herein are glycopyrrolate base compositions comprising aselected mixture of stereoisomers useful in the production ofglycopyrronium tosylate. In an embodiment, provided herein is aglycopyrrolate base composition comprising threo-glycopyrrolate base anderythro-glycopyrrolate base, wherein the threo-glycopyrrolate base is atleast 95% of the total glycopyrrolate base content of the compositionand the erythro-glycopyrrolate base is less than 5% of the totalglycopyrrolate base content of the composition.

Also provided herein are glycopyrronium tosylate compositions useful forthe treatment of, among other conditions, hyperhidrosis. In anembodiment, provided herein is a glycopyrronium tosylate compositioncomprising threo-glycopyrronium tosylate and erythro-glycopyrroniumtosylate, wherein the threo-glycopyrronium tosylate is at least 95% ofthe total glycopyrronium tosylate content of the composition and theerythro-glycopyrronium tosylate is less than 5% of the totalglycopyrrolate base content of the composition.

DESCRIPTION OF EXEMPLARY EMBODIMENTS

Provided herein are methods of producing glycopyrronium tosylate usefulfor hyperhidrosis.

Definitions

When referring to the methods and compounds described herein, thefollowing terms have the following meanings unless indicated otherwise.Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. In the event that there is a plurality of definitions for aterm herein, those in this section prevail unless stated otherwise.

As used herein, and unless otherwise specified, the term“glycopyrrolate” refers to a cation of a salt containing glycopyrronium.In other words, as used herein, “glycopyrrolate” and “glycopyrronium”are used interchangeably. For example, “glycopyrrolate tosylate” and“glycopyrronium tosylate” refer to the same salt.

As used herein, and unless otherwise specified, the term “glycopyrroniumtosylate” refers to a tosylate salt of glycopyrronium. This tosylatesalt can be referred to as“3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl-pyrrolidiniumtosylate,” or as“3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate.” The term “glycopyrronium tosylate” refers tothe chemical structure:

Furthermore, the term “glycopyrronium tosylate” as used herein, andunless otherwise specified, includes any one of the four diastereomerslisted below as well as any mixture of two, three, or four of thefollowing diastereomers:

(R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate:

(S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate:

(R)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate:

and

(S)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate:

In one embodiment, the “glycopyrronium tosylate” is(R)-3-(S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate. In another embodiment, the “glycopyrroniumtosylate” is(S)-3-(R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate. In another embodiment, the “glycopyrroniumtosylate” is(R)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate. In another embodiment, the “glycopyrroniumtosylate” is(S)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate. In one embodiment, the “glycopyrroniumtosylate” is(R)-3-(S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate and(S)-3-(R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate. In another embodiment, the “glycopyrroniumtosylate” is(R)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate and(S)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate.

As used herein, the term “threo-glycopyrronium tosylate” refers to amixture of(R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate and(S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate. In certain embodiments “threo-glycopyrroniumtosylate” is a racemic mixture of(R)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate and(S)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate.

As used herein, the term “erythro-glycopyrronium tosylate” refers to amixtureof(R)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate and(S)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate. In certain embodiments,“erythro-glycopyrronium tosylate” is a racemic mixture of(R)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium4-methylbenzenesulfonate and(S)-3-((S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-di-methylpyrrolidinium4-methylbenzenesulfonate.

In an embodiment, the “glycopyrronium tosylate” is threo-glycopyrroniumtosylate or erythro-glycopyrronium tosylate. In an embodiment, the“glycopyrronium tosylate” is threo-glycopyrronium tosylate. In anembodiment, the “glycopyrronium tosylate” is erythro-glycopyrroniumtosylate.

The terms “substantially free of” and “substantially in the absence of,”when used in connection with an article (including, but not limited to,a compound, a salt thereof, a solvate thereof, a solid form thereof, acomposition, a mixture of stereoisomers, and the like), refers to thearticle that includes at least 85% or 90% by weight, in certainembodiments, 95%, 98%, 99%, or 100% by weight, of the designatedarticle. For example, the term “substantially free of” or “substantiallyin the absence of” with respect to a glycopyrronium tosylate compositioncan refer to a glycopyrronium tosylate composition that includes atleast 85% or 90% by weight, in certain embodiments, 95%, 98%, 99%, or100% by weight, of the designated diastereomer, or mixture ofdiastereomers, of glycopyrronium tosylate. In certain embodiments, inthe methods, compounds, and compositions provided herein, the compoundsor compositions are substantially free of undesignated enantiomers orother compounds or mixtures of enantiomers.

Similarly, the term “isolated” with respect to a glycopyrronium tosylatecomposition refers to a glycopyrronium tosylate composition thatincludes at least 85%, 90%, 95%, 98%, or 99% to 100% by weight, of theglycopyrronium tosylate, the remainder comprising other chemical speciesor enantiomers.

Methods

Provided herein are methods of producing glycopyrronium tosylate.Glycopyrronium tosylate is useful for the treatment of hyperhidrosis.

In an aspect, provided herein are methods of producing glycopyrroniumtosylate comprising contacting glycopyrrolate base with methyl tosylateto produce glycopyrronium tosylate:

In certain embodiments, the glycopyrrolate base contacted with methyltosylate is contacted with an organic solvent. In an embodiment, theorganic solvent is a water-miscible organic solvent. In an embodiment,the organic solvent is a water-miscible aldehyde, organic acid, ketone,nitrile, diol, alcohol, aminoalcohol, glycol, sulfoxide, ether, cyclicether, cyclic diether, amine, polyol, or cyclic amine comprising from 1to 6 carbon atoms. In an embodiment, the organic solvent isacetaldehyde, acetic acid, acetone, acetonitrile, 1,2-butanediol,1,3-butanediol, 1,4-butanediol, 2-butoxyethanol, butyric acid,diethanolamine, diethylenetriamine, dimethylformamide, dimethoxyethane,dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, ethylamine,ethylene glycol, formic acid, furfuryl alcohol, glycerol, methanol,methyl diethanolamine, methyl isocyanide, 1-propanol, 1,3-propanediol,1,5-pentanediol, 2-propanol, propanoic acid, propylene glycol, pyridine,tetrahydrofuran, or triethylene glycol. In an embodiment, the organicsolvent is a water-miscible aldehyde, ketone, or ester comprising from 2to 5 carbon atoms. In an embodiment, the organic solvent is acetone orethyl acetate. In certain embodiments, the organic solvent is acetone.In certain embodiments, the organic solvent is ethyl acetate.

In an embodiment, the reaction is conducted for at least 2 to 4 hours,optionally at least 2.5 to 3.5 hours, optionally for at least about 3hours. In an embodiment, the reaction is conducted for about 3 to 21hours, optionally for about 6 to 18 hours, optionally for about 9 to 15hours, optionally for about 11 to 13 hours, optionally for about 12hours. In an embodiment, the reaction is conducted at a temperatureselected over the range of 20° C. to 26 ° C., optionally 22° C. to 24°C., optionally conducted at about 23° C., optionally conducted at about25° C.

In certain embodiments, the glycopyrronium tosylate produced issubstantially in the absence of erythro-glycopyrronium tosylate. Incertain embodiments, the glycopyrronium tosylate is isolatedthreo-glycopyrronium tosylate. In certain embodiments, theglycopyrronium tosylate is a mixture of threo-glycopyrronium tosylateand erythro-glycopyrronium tosylate, and the threo-glycopyrroniumtosylate is at least 95% of the total glycopyrronium tosylate mixtureand the erythro-glycopyrronium tosylate is less than 5% of the totalglycopyrronium tosylate mixture. In certain embodiments, thethreo-glycopyrronium tosylate is at least 96% of the totalglycopyrronium tosylate mixture and the erythro-glycopyrronium tosylateis less than 4% of the total glycopyrronium tosylate mixture. In certainembodiments, the threo-glycopyrronium tosylate is at least 97% of thetotal glycopyrronium tosylate mixture and the erythro-glycopyrroniumtosylate is less than 3% of the total glycopyrronium tosylate mixture.

In certain embodiments, the glycopyrronium tosylate is purified by oneor more crystallizations in an aqueous solvent. In certain embodiments,the aqueous solvent is water. In certain embodiments, the aqueoussolvent is water and the glycopyrronium tosylate is purified as isolatedthreo-glycopyrronium tosylate monohydrate. In certain embodiments, thepurified glycopyrronium tosylate is substantially pure. In certainembodiments, the purified glycopyrronium tosylate is a mixture ofthreo-glycopyrronium tosylate and erythro-glycopyrronium tosylate, andthe threo-glycopyrronium tosylate is at least 99% of the totalglycopyrronium tosylate in the mixture and the erythro-glycopyrroniumtosylate is less than 1% of the total glycopyrronium tosylate in themixture. In certain embodiments, the threo-glycopyrronium tosylate is atleast 99.5% of the total glycopyrronium tosylate in the mixture and theerythro-glycopyrronium tosylate is less than 0.5% of the totalglycopyrronium tosylate in the mixture. In certain embodiments, thethreo-glycopyrronium tosylate is at least 99.6% of the totalglycopyrronium tosylate in the mixture and the erythro-glycopyrroniumtosylate is less than 0.4% of the total glycopyrronium tosylate in themixture.

In certain embodiments, the glycopyrrolate base is produced bycontacting a glycopyrrolate base, 5-nitroisophthalate salt with aninorganic base to form the glycopyrrolate base:

Without wishing to be bound by theory, it is believedthreo-glycopyrrolate base, 5-nitroisophthalate salt is less soluble inan organic solvent than erythro-glycopyrrolate base, 5-nitrosiophthalatesalt and that this difference in solubility can be used to isolate andpurify the threo-glycopyrrolate base. Therefore, in certain embodiments,the glycopyrrolate base, 5-nitroisophthalate salt and inorganic base arecontacted with an organic solvent. In certain embodiments, the organicsolvent is a water-immiscible organic solvent. In certain embodiments,the water-immiscible organic solvent is benzene, n-butanol, carbontetrachloride, chloroform, cyclohexane, ethylene chloride, heptane,hexane, pentane, toluene, trichloroethylene, or xylene. In certainembodiments, the organic solvent is toluene. In certain embodiments, theinorganic base is aqueous sodium hydroxide. In certain embodiments, theglycopyrrolate base is produced as a mixture of threo-glycopyrrolatebase and erythro-glycopyrrolate base, and the threo-glycopyrrolate baseis at least 95% of the total glycopyrrolate base produced and theerythro-glycopyrrolate base is less than 5% of the total glycopyrrolatebase produced. In certain embodiments, the threo-glycopyrrolate base isat least 96% of the total glycopyrrolate base produced and theerythro-glycopyrrolate base is less than 4% of the total glycopyrrolatebase produced. In certain embodiments, the threo-glycopyrrolate base isat least 97% of the total glycopyrrolate base produced and theerythro-glycopyrrolate base is less than 3% of the total glycopyrrolatebase produced.

In an embodiment, the reaction is conducted at a temperature selectedover the range of 20° C. to 26° C., optionally 22° C. to 24° C.,optionally at about 23° C., optionally at about 25° C. In an embodiment,the reaction mixture is stirred for 5 to 20 minutes, optionally 10 to 15minutes, optionally 15 minutes. In an embodiment, the pH of the solutionin which the reaction is conducted is measured and adjusted to liewithin a selected pH range. In an embodiment, the pH range is 11.0 to13.0, optionally 11.2 to 12.8, optionally 11.5 to 12.5, optionally about12.0.

In certain embodiments, the glycopyrrolate base, 5-nitroisophthalatesalt is produced by contacting a glycopyrrolate base with5-nitroisophthalic acid to form the glycopyrrolate base,5-nitroisophthalate salt:

In certain embodiments, the glycopyrrolate base and 5-nitroisophthalicacid are contacted with methanol. In certain embodiments, theglycopyrrolate base, 5-nitroisophthalate salt produced is substantiallyin the absence of erythro-glycopyrrolate base, 5-nitroisophthalate salt.In an embodiment, the glycopyrrolate base, 5-nitroisophthalate salt isproduced as a mixture of threo-glycopyrrolate base, 5-nitroisophthalatesalt and erythro-glycopyrrolate base, 5-nitroisophthalate salt, whereinthe threo-glycopyrrolate base, 5-nitroisophthalate salt is at least 95%of the total glycopyrrolate base, 5-nitroisophthalate salt produced, andthe erythro-glycopyrrolate base, 5-nitroisophthalate salt is less than5% of the total glycopyrrolate base, 5-nitroisophthalate salt produced.In an embodiment, the threo-glycopyrrolate base, 5-nitroisophthalatesalt is at least 96% of the total glycopyrrolate base,5-nitroisophthalate salt produced and the erythro-glycopyrrolate base,5-nitroisophthalate salt is less than 4% of the total glycopyrrolatebase, 5-nitroisophthalate salt produced. In an embodiment, thethreo-glycopyrrolate base, 5-nitroisophthalate salt is at least 97% ofthe total glycopyrrolate base, 5-nitroisophthalate salt produced and theerythro-glycopyrrolate base, 5-nitroisophthalate salt is less than 3% ofthe total glycopyrrolate base, 5-nitroisophthalate salt produced.

In an embodiment, the reaction is conducted for 3 to 5 hours, optionallyfor 3.5 to 4.5 hours, optionally for about 4 hours. In an embodiment,the reaction is conducted at a temperature selected over the range of20° C. to 26° C., optionally 22° C. to 24° C., optionally at about 23°C., optionally at about 25° C.

In certain embodiments, the glycopyrrolate base is produced bycontacting cyclopentylmandelic acid with 1-methylpyrrolidin-3-ol to formthe glycopyrrolate base:

In an embodiment, the glycopyrrolate base is produced as a mixture ofthreo-glycopyrrolate base and erythro-glycopyrrolate base. In anembodiment, the glycopyrrolate base is produced as a racemic mixture ofthreo-glycopyrrolate base and erythro-glycopyrrolate base.

In an aspect, provided herein is a method of producing glycopyrroniumtosylate comprising:

(i) contacting cyclopentylmandelic acid with 1-methylpyrrolidin-3-ol toform glycopyrrolate base:

(ii) contacting the glycopyrrolate base with 5-nitroisophthalic acid toform glycopyrrolate base, 5-nitroisophthalate salt:

(iii) contacting the glycopyrrolate base, 5-nitroisophthalate salt withan inorganic base to form glycopyrrolate base:

and

(iv) contacting the glycopyrrolate base with methyl tosylate to produceglycopyrronium tosylate:

In an embodiment, the glycopyrrolate base formed in step (i) is amixture of four diastereomers (i.e., comprises both the threo anderythro pairs of diastereomers). In an embodiment, the glycopyrrolatebase formed in step (i) is a racemic mixture of four diastereomers(i.e., comprises equal amounts of both the threo and erythro pairs ofdiastereomers).

In and embodiment, the glycopyrrolate base, 5-nitroisophthalate saltproduced in step (ii) is substantially in the absence oferythro-glycopyrrolate base, 5-nitroisophthalate salt. In an embodiment,the glycopyrrolate base, 5-nitroisophthalate salt formed in step (ii) isproduced as a mixture of threo-glycopyrrolate base, 5-nitroisophthalatesalt and erythro-glycopyrrolate base, 5-nitroisophthalate salt, whereinthe threo-glycopyrrolate base, 5-nitroisophthalate salt is at least 95%of the total glycopyrrolate base, 5-nitroisophthalate salt produced, andthe erythro-glycopyrrolate base, 5-nitroisophthalate salt is less than5% of the total glycopyrrolate base, 5-nitroisophthalate salt produced.In an embodiment, the threo-glycopyrrolate base, 5-nitroisophthalatesalt is at least 96% of the total glycopyrrolate base,5-nitroisophthalate salt produced and the erythro-glycopyrrolate base,5-nitroisophthalate salt is less than 4% of the total glycopyrrolatebase, 5-nitroisophthalate salt produced. In an embodiment, thethreo-glycopyrrolate base, 5-nitroisophthalate salt is at least 97% ofthe total glycopyrrolate base, 5-nitroisophthalate salt produced and theerythro-glycopyrrolate base, 5-nitroisophthalate salt is less than 3% ofthe total glycopyrrolate base, 5-nitroisophthalate salt produced.

Without wishing to be bound by theory, it is believedthreo-glycopyrrolate base, 5-nitroisophthalate salt is less soluble inan organic solvent than erythro-glycopyrrolate base, 5-nitrosiophthalatesalt and that this difference in solubility can be used to isolate andpurify the threo-glycopyrrolate base. Therefore, in an embodiment, instep (iii) the glycopyrrolate base, 5-nitroisophthalate salt andinorganic base are contacted with an organic solvent. In certainembodiments, the organic solvent is a water-immiscible organic solvent.In certain embodiments, the water-immiscible organic solvent is benzene,n-butanol, carbon tetrachloride, chloroform, cyclohexane, ethylenechloride, heptane, hexane, pentane, toluene, trichloroethylene, orxylene. In an embodiment, the organic solvent is toluene.

In an embodiment, in step (iii) the inorganic base is aqueous sodiumhydroxide. In an embodiment, in step (iii) the inorganic base is aqueoussodium hydroxide and the glycopyrrolate base, 5-nitroisophthalate saltand inorganic base are contacted with an organic solvent. In certainembodiments, the organic solvent is a water-immiscible organic solvent.In certain embodiments, the water-immiscible organic solvent is benzene,n-butanol, carbon tetrachloride, chloroform, cyclohexane, ethylenechloride, heptane, hexane, pentane, toluene, trichloroethylene, orxylene. In an embodiment, the organic solvent is toluene.

In an embodiment, the glycopyrrolate base produced in step (iii) isproduced as a mixture of threo-glycopyrrolate base anderythro-glycopyrrolate base, the threo-glycopyrrolate base is at least95% of the total glycopyrrolate base produced, and theerythro-glycopyrrolate base is less than 5% of the total glycopyrrolatebase produced. In an embodiment, the threo-glycopyrrolate base is atleast 96% of the total glycopyrrolate base produced and theerythro-glycopyrrolate base is less than 4% of the total glycopyrrolatebase produced. In an embodiment, the threo-glycopyrrolate base is atleast 97% of the total glycopyrrolate base produced and theerythro-glycopyrrolate base is less than 3% of the total glycopyrrolatebase produced.

In an embodiment, the glycopyrronium tosylate produced in step (iv) isproduced as a mixture of threo-glycopyrronium tosylate anderythro-glycopyrronium tosylate, wherein the threo-glycopyrroniumtosylate is at least 95% of the total glycopyrronium tosylate mixture,and the erythro-glycopyrronium tosylate is less than 5% of the totalglycopyrronium tosylate mixture. In an embodiment, thethreo-glycopyrronium tosylate is at least 96% of the totalglycopyrronium tosylate mixture and the erythro-glycopyrronium tosylateis less than 4% of the total glycopyrronium tosylate mixture. In anembodiment, the threo-glycopyrronium tosylate is at least 97% of thetotal glycopyrronium tosylate mixture and the erythro-glycopyrroniumtosylate is less than 3% of the total glycopyrronium tosylate mixture.

In an embodiment, the glycopyrronium tosylate is purified by one or more(re)crystallizations in an aqueous solvent. In an embodiment, theaqueous solvent is water. In an embodiment, the glycopyrronium tosylatefollowing (re)crystallization in water is in the form of glycopyrroniumtosylate monohydrate. In an embodiment, the amount of water in theglycopyrronium tosylate monohydrate is less than about 5% weight waterto weight glycopyrronium tosylate, optionally less than about 4% weightwater to weight glycopyrronium tosylate, optionally about 3.5% weightwater to weight glycopyrronium tosylate. In an embodiment, the purifiedglycopyrronium tosylate is a mixture of threo-glycopyrronium tosylateand erythro-glycopyrronium tosylate, wherein the threo-glycopyrroniumtosylate is at least 99% of the total glycopyrronium tosylate in themixture, and the erythro-glycopyrronium tosylate is less than 1% of thetotal glycopyrronium tosylate in the mixture. In an embodiment, thethreo-glycopyrronium tosylate is at least 99.5% of the totalglycopyrronium tosylate in the mixture and the erythro-glycopyrroniumtosylate is less than 0.5% of the total glycopyrronium tosylate in themixture. In an embodiment, the threo-glycopyrronium tosylate is at least99.6% of the total glycopyrronium tosylate in the mixture and theerythro-glycopyrronium tosylate is less than 0.4% of the totalglycopyrronium tosylate in the mixture.

In an embodiment, in step (iv) the glycopyrrolate base and methyltosylate are contacted with an organic solvent. In certain embodiments,the glycopyrrolate base contacted with methyl tosylate is contacted withan organic solvent. In an embodiment, the organic solvent is awater-miscible organic solvent. In an embodiment, the organic solvent isa water-miscible aldehyde, organic acid, ketone, nitrile, diol, alcohol,aminoalcohol, glycol, sulfoxide, ether, cyclic ether, cyclic diether,amine, polyol, or cyclic amine comprising from 1 to 6 carbon atoms. Inan embodiment, the organic solvent is acetaldehyde, acetic acid,acetone, acetonitrile, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol,2-butoxyethanol, butyric acid, diethanolamine, diethylenetriamine,dimethylformamide, dimethoxyethane, dimethyl sulfoxide, 1,4-dioxane,ethanol, ethyl acetate, ethylamine, ethylene glycol, formic acid,furfuryl alcohol, glycerol, methanol, methyl diethanolamine, methylisocyanide, 1-propanol, 1,3-propanediol, 1,5-pentanediol, 2-propanol,propanoic acid, propylene glycol, pyridine, tetrahydrofuran, ortriethylene glycol. In an embodiment, the organic solvent is awater-miscible aldehyde, ketone, or ester comprising from 2 to 5 carbonatoms. In an embodiment, the organic solvent is acetone or ethylacetate. In certain embodiments, the organic solvent is acetone. Incertain embodiments, the organic solvent is ethyl acetate.

In an embodiment, the reaction in step (ii) is conducted for 3 to 5hours, optionally for 3.5 to 4.5 hours, optionally for about 4 hours. Inan embodiment, the reaction in step (ii) is conducted at a temperatureselected over the range of 20° C. to 26° C., optionally 22° C. to 24 °C., optionally at about 23° C., optionally at about 25° C.

In an embodiment, the reaction in step (iii) is conducted at atemperature selected over the range of 20° C. to 26° C., optionally 22°C. to 24° C., optionally at about 23° C., optionally at about 25° C. Inan embodiment, the reaction mixture in step (iii) is stirred for 5 to 20minutes, optionally 10 to 15 minutes, optionally 15 minutes. In anembodiment, the pH of the solution in which the reaction in step (iii)is conducted is measured and adjusted to lie within a selected pH range.In an embodiment, the pH range is 11.0 to 13.0, optionally 11.2 to 12.8,optionally 11.5 to 12.5, optionally about 12.0.

In an embodiment, the reaction in step (iv) is conducted for at least 2to 4 hours, optionally at least 2.5 to 3.5 hours, optionally for atleast about 3 hours. In an embodiment, the reaction in step (iv) isconducted for about 3 to 21 hours, optionally for about 6 to 18 hours,optionally for about 9 to 15 hours, optionally for about 11 to 13 hours,optionally for about 12 hours. In an embodiment, the reaction in step(iv) is conducted at a temperature selected over the range of 20° C. to26° C., optionally 22° C. to 24° C., optionally conducted at about 23°C., optionally conducted at about 25° C.

Compositions

Provided herein are glycopyrronium tosylate compositions andcompositions useful in the preparation of glycopyrronium tosylate.

In an aspect, provided herein is a glycopyrrolate base compositioncomprising threo-glycopyrrolate base and erythro-glycopyrrolate base,wherein the composition is produced by:

(i) contacting cyclopentylmandelic acid with 1-methylpyrrolidin-3-ol toform glycopyrrolate base:

(ii) contacting the glycopyrrolate base with 5-nitroisophthalic acid toform glycopyrrolate base, 5-nitroisophthalate salt:

(iii) contacting the glycopyrrolate base, 5-nitroisophthalate salt withan inorganic base to form glycopyrrolate base: and

In an embodiment, the glycopyrrolate base formed in step (i) is amixture of four diastereomers (i.e., comprises both the threo anderythro pairs of diastereomers). In an embodiment, the glycopyrrolatebase formed in step (i) is a racemic mixture of four diastereomers(i.e., comprises equal amounts of both the threo and erythro pairs ofdiastereomers).

In an embodiment, the glycopyrrolate base, 5-nitroisophthalate saltformed in step (ii) is produced as a mixture of threo-glycopyrrolatebase, 5-nitroisophthalate salt and erythro-glycopyrrolate base,5-nitroisophthalate salt, wherein the threo-glycopyrrolate base,5-nitroisophthalate salt is at least 95% of the total glycopyrrolatebase, 5-nitroisophthalate salt produced, and the erythro-glycopyrrolatebase, 5-nitroisophthalate salt is less than 5% of the totalglycopyrrolate base, 5-nitroisophthalate salt produced. In anembodiment, the threo-glycopyrrolate base, 5-nitroisophthalate salt isat least 96% of the total glycopyrrolate base, 5-nitroisophthalate saltproduced and the erythro-glycopyrrolate base, 5-nitroisophthalate saltis less than 4% of the total glycopyrrolate base, 5-nitroisophthalatesalt produced. In an embodiment, the threo-glycopyrrolate base,5-nitroisophthalate salt is at least 97% of the total glycopyrrolatebase, 5-nitroisophthalate salt produced and the erythro-glycopyrrolatebase, 5-nitroisophthalate salt is less than 3% of the totalglycopyrrolate base, 5-nitroisophthalate salt produced.

Without wishing to be bound by theory, it is believedthreo-glycopyrrolate base, 5-nitroisophthalate salt is less soluble inan organic solvent than erythro-glycopyrrolate base, 5-nitroisophthalatesalt and that this difference in solubility can be used to isolate andpurify the threo-glycopyrrolate base. Therefore, in an embodiment, instep (iii) the glycopyrrolate base, 5-nitroisophthalate salt andinorganic base are contacted with an organic solvent. In certainembodiments, the organic solvent is a water-immiscible organic solvent.In certain embodiments, the water-immiscible organic solvent is benzene,n-butanol, carbon tetrachloride, chloroform, cyclohexane, ethylenechloride, heptane, hexane, pentane, toluene, trichloroethylene, orxylene. In an embodiment, the organic solvent is toluene. In anembodiment, in step (iii) the inorganic base is aqueous sodiumhydroxide. In an embodiment, the threo-glycopyrrolate base is at least95% of the total glycopyrrolate base content of the composition and theerythro-glycopyrrolate base is less than 5% of the total glycopyrrolatebase content of the composition. In an embodiment, thethreo-glycopyrrolate base is at least 96% of the total glycopyrrolatebase content of the composition and the erythro-glycopyrrolate base isless than 4% of the total glycopyrrolate base content of thecomposition. In an embodiment, the threo-glycopyrrolate base is at least97% of the total glycopyrrolate base content of the composition and theerythro-glycopyrrolate base is less than 3% of the total glycopyrrolatebase content of the composition.

In an aspect, provided herein is a glycopyrronium tosylate compositioncomprising threo-glycopyrronium tosylate and erythro-glycopyrroniumtosylate, wherein the threo-glycopyrronium tosylate is at least 95% ofthe total glycopyrronium tosylate content of the composition and theerythro-glycopyrronium tosylate is less than 5% of the totalglycopyrrolate base content of the composition. In an embodiment, thethreo-glycopyrronium tosylate is at least 96% of the totalglycopyrronium tosylate content of the composition and theerythro-glycopyrronium tosylate is less than 4% of the totalglycopyrronium tosylate content of the composition. In an embodiment,the threo-glycopyrronium tosylate is at least 97% of the totalglycopyrronium tosylate content of the composition and theerythro-glycopyrronium tosylate is less than 3% of the totalglycopyrronium tosylate content of the composition. In an embodiment,the threo-glycopyrronium tosylate is at least 99% of the totalglycopyrronium tosylate content of the composition and theerythro-glycopyrronium tosylate is less than 1% of the totalglycopyrronium tosylate content of the composition. In an embodiment,the threo-glycopyrronium tosylate is at least 99.5% of the totalglycopyrronium tosylate content of the composition and theerythro-glycopyrronium tosylate is less than 0.5% of the totalglycopyrronium tosylate content of the composition. In an embodiment,the threo-glycopyrronium tosylate is at least 99.6% of the totalglycopyrronium tosylate content of the composition and theerythro-glycopyrronium tosylate is less than 0.4% of the totalglycopyrronium tosylate content of the composition.

In an aspect, provided herein is a glycopyrronium tosylate compositioncomprising threo-glycopyrronium tosylate and erythro-glycopyrroniumtosylate, wherein:

the threo-glycopyrronium tosylate is at least 95% of the totalglycopyrronium tosylate content of the composition;

the erythro-glycopyrronium tosylate is less than 5% of the totalglycopyrronium base content of the composition; and

the composition is produced by:

(i) contacting cyclopentylmandelic acid with 1-methylpyrrolidin-3-ol toform glycopyrrolate base:

(ii) contacting the glycopyrrolate base with 5-nitroisophthalic acid toform glycopyrrolate base, 5-nitroisophthalate salt:

(iii) contacting the glycopyrrolate base, 5-nitroisophthalate salt withan inorganic base to form glycopyrrolate base:

and

(iv) contacting the glycopyrrolate base with methyl tosylate to produceglycopyrronium tosylate:

Without wishing to be bound by theory, it is believedthreo-glycopyrrolate base, 5-nitroisophthalate salt is less soluble inan organic solvent than erythro-glycopyrrolate base, 5-nitroisophthalatesalt and that this difference in solubility can be used to isolate andpurify the threo-glycopyrrolate base. Therefore, in an embodiment, instep (iii) the glycopyrrolate base, 5-nitroisophthalate salt andinorganic base are contacted with an organic solvent. In certainembodiments, the organic solvent is a water-immiscible organic solvent.In certain embodiments, the water-immiscible organic solvent is benzene,n-butanol, carbon tetrachloride, chloroform, cyclohexane, ethylenechloride, heptane, hexane, pentane, toluene, trichloroethylene, orxylene. In an embodiment, the organic solvent is toluene. In anembodiment, in step (iii) the inorganic base is aqueous sodiumhydroxide. In an embodiment, the glycopyrrolate base produced in step(iii) is produced as a mixture of threo-glycopyrrolate base anderythro-glycopyrrolate base, wherein the threo-glycopyrrolate base is atleast 95% of the total glycopyrrolate base produced, and theerythro-glycopyrrolate base is less than 5% of the total glycopyrrolatebase produced. In an embodiment, the threo-glycopyrrolate base is atleast 96% of the total glycopyrrolate base produced and theerythro-glycopyrrolate base is less than 4% of the total glycopyrrolatebase produced. In an embodiment, the threo-glycopyrrolate base is atleast 97% of the total glycopyrrolate base produced and theerythro-glycopyrrolate base is less than 3% of the total glycopyrrolatebase produced.

In an embodiment, the glycopyrrolate base formed in step (i) is amixture of four diastereomers (i.e., comprises both the threo anderythro pairs of diastereomers). In an embodiment, the glycopyrrolatebase formed in step (i) is a racemic mixture of four diastereomers(i.e., comprises equal amounts of both the threo and erythro pairs ofdiastereomers).

In an embodiment, the glycopyrrolate base, 5-nitroisophthalate saltformed in step (ii) is produced as a mixture of threo-glycopyrrolatebase, 5-nitroisophthalate salt and erythro-glycopyrrolate base,5-nitroisophthalate salt, wherein the threo-glycopyrrolate base,5-nitroisophthalate salt is at least 95% of the total glycopyrrolatebase, 5-nitroisophthalate salt produced, and the erythro-glycopyrrolatebase, 5-nitroisophthalate salt is less than 5% of the totalglycopyrrolate base, 5-nitroisophthalate salt produced. In anembodiment, the threo-glycopyrrolate base, 5-nitroisophthalate salt isat least 96% of the total glycopyrrolate base, 5-nitroisophthalate saltproduced and the erythro-glycopyrrolate base, 5-nitroisophthalate saltis less than 4% of the total glycopyrrolate base, 5-nitroisophthalatesalt produced. In an embodiment, the threo-glycopyrrolate base,5-nitroisophthalate salt is at least 97% of the total glycopyrrolatebase, 5-nitroisophthalate salt produced and the erythro-glycopyrrolatebase, 5-nitroisophthalate salt is less than 3% of the totalglycopyrrolate base, 5-nitroisophthalate salt produced.

In an embodiment, the glycopyrronium tosylate produced in step (iv) isproduced as a mixture of threo-glycopyrronium tosylate anderythro-glycopyrronium tosylate, wherein the threo-glycopyrroniumtosylate is at least 95% of the total glycopyrronium tosylate mixture,and the erythro-glycopyrronium tosylate is less than 5% of the totalglycopyrronium tosylate mixture. In an embodiment, thethreo-glycopyrronium tosylate is at least 96% of the totalglycopyrronium tosylate mixture and the erythro-glycopyrronium tosylateis less than 4% of the total glycopyrronium tosylate mixture. In anembodiment, the threo-glycopyrronium tosylate is at least 97% of thetotal glycopyrronium tosylate mixture and the erythro-glycopyrroniumtosylate is less than 3% of the total glycopyrronium tosylate mixture.

In an embodiment, the glycopyrronium tosylate is purified by one or more(re)crystallizations in an aqueous solvent. In an embodiment, theaqueous solvent is water. In an embodiment, the glycopyrronium tosylatefollowing (re)crystallization in water is in the form of glycopyrroniumtosylate monohydrate. In an embodiment, the amount of water in theglycopyrronium tosylate monohydrate is less than about 5% weight waterto weight glycopyrronium tosylate, optionally less than about 4% weightwater to weight glycopyrronium tosylate, optionally about 3.5% weightwater to weight glycopyrronium tosylate. In an embodiment, the purifiedglycopyrronium tosylate is a mixture of threo-glycopyrronium tosylateand erythro-glycopyrronium tosylate, wherein the threo-glycopyrroniumtosylate is at least 99% of the total glycopyrronium tosylate in themixture, and the erythro-glycopyrronium tosylate is less than 1% of thetotal glycopyrronium tosylate in the mixture. In an embodiment, thethreo-glycopyrronium tosylate is at least 99.5% of the totalglycopyrronium tosylate in the mixture and the erythro-glycopyrroniumtosylate is less than 0.5% of the total glycopyrronium tosylate in themixture. In an embodiment, the threo-glycopyrronium tosylate is at least99.6% of the total glycopyrronium tosylate in the mixture and theerythro-glycopyrronium tosylate is less than 0.4% of the totalglycopyrronium tosylate in the mixture.

In an embodiment, in step (iv) the glycopyrrolate base and methyltosylate are contacted with an organic solvent. In certain embodiments,the glycopyrrolate base contacted with methyl tosylate is contacted withan organic solvent. In an embodiment, the organic solvent is awater-miscible organic solvent. In an embodiment, the organic solvent isa water-miscible aldehyde, organic acid, ketone, nitrile, diol, alcohol,aminoalcohol, glycol, sulfoxide, ether, cyclic ether, cyclic diether,amine, polyol, or cyclic amine comprising from 1 to 6 carbon atoms. Inan embodiment, the organic solvent is acetaldehyde, acetic acid,acetone, acetonitrile, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol,2-butoxyethanol, butyric acid, diethanolamine, diethylenetriamine,dimethylformamide, dimethoxyethane, dimethyl sulfoxide, 1,4-dioxane,ethanol, ethyl acetate, ethylamine, ethylene glycol, formic acid,furfuryl alcohol, glycerol, methanol, methyl diethanolamine, methylisocyanide, 1-propanol, 1,3-propanediol, 1,5-pentanediol, 2-propanol,propanoic acid, propylene glycol, pyridine, tetrahydrofuran, ortriethylene glycol. In an embodiment, the organic solvent is awater-miscible aldehyde, ketone, or ester comprising from 2 to 5 carbonatoms. In an embodiment, the organic solvent is acetone or ethylacetate. In certain embodiments, the organic solvent is acetone. Incertain embodiments, the organic solvent is ethyl acetate.

In certain embodiments, the glycopyrronium tosylate composition issubstantially free of erythro-glycopyrronium tosylate. In an embodiment,at least 90% of the glycopyrronium tosylate in the composition isthreo-glycopyrronium tosylate. In an embodiment, at least 91% of theglycopyrronium tosylate in the composition is threo-glycopyrroniumtosylate. In an embodiment, at least 92% of the glycopyrronium tosylatein the composition is threo-glycopyrronium tosylate. In an embodiment,at least 93% of the glycopyrronium tosylate in the composition isthreo-glycopyrronium tosylate. In an embodiment, at least 94% of theglycopyrronium tosylate in the composition is threo-glycopyrroniumtosylate. In an embodiment, at least 95% of the glycopyrronium tosylatein the composition is threo-glycopyrronium tosylate. In an embodiment,at least 96% of the glycopyrronium tosylate in the composition isthreo-glycopyrronium tosylate. In an embodiment, at least 97% of theglycopyrronium tosylate in the composition is threo-glycopyrroniumtosylate. In an embodiment, at least 98% of the glycopyrronium tosylatein the composition is threo-glycopyrronium tosylate. In an embodiment,at least 99% of the glycopyrronium tosylate in the composition isthreo-glycopyrronium tosylate.

Methods of Treatment

Provided herein are methods of treating a disorder comprisingadministering an effective treatment amount of a glycopyrronium tosylatecomposition described herein. In an embodiment, provided herein is amethod of treating hyperhidrosis comprising administering an effectivetreatment amount of a glycopyrronium tosylate composition describedherein. In an embodiment, provided herein is a method of treatinghyperhidrosis comprising administering an effective treatment amount ofa glycopyrronium tosylate composition described herein, wherein theglycopyrronium tosylate composition is administered topically. In anembodiment, provided herein is a method of treating hyperhidrosiscomprising administering an effective treatment amount of aglycopyrronium tosylate composition described herein, wherein theglycopyrronium tosylate composition is administered topically with awipe.

Pharmaceutical Compositions and Methods of Administration

The glycopyrronium tosylate compositions can be formulated intopharmaceutical compositions using methods available in the art and thosedisclosed herein. Any of the glycopyrronium tosylate compositionsdisclosed herein can be provided in the appropriate pharmaceuticalcomposition and be administered by a suitable route of administration.

The methods provided herein encompass administering pharmaceuticalcompositions containing at least one glycopyrronium tosylate compositionas described herein, either used alone or in the form of a combinationwith one or more compatible and pharmaceutically acceptable carriers,such as diluents or adjuvants, or with another therapeutic agent.

In certain embodiments, the second agent can be formulated or packagedwith the glycopyrronium tosylate composition provided herein. Of course,the second agent will only be formulated with the glycopyrroniumtosylate composition provided herein when, according to the judgment ofthose of skill in the art, such co-formulation should not interfere withthe activity of either agent or the method of administration. In certainembodiments, the glycopyrronium tosylate composition provided herein andthe second agent are formulated separately. They can be packagedtogether, or packaged separately, for the convenience of thepractitioner of skill in the art.

In clinical practice the active agents provided herein may beadministered by any conventional route. In certain embodiments, theglycopyrronium tosylate composition provided herein is administeredtopically. In certain embodiments, the glycopyrronium tosylatecomposition provided herein is administered topically with a wipe.

In certain embodiments, a composition provided herein is apharmaceutical composition. Pharmaceutical compositions provided hereincomprise a prophylactically or therapeutically effective amount of oneor more prophylactic or therapeutic agents (e.g., a glycopyrroniumtosylate composition provided herein, or other prophylactic ortherapeutic agent), and typically one or more pharmaceuticallyacceptable carriers or excipients. In a specific embodiment and in thiscontext, the term “pharmaceutically acceptable” means approved by aregulatory agency of a government, or listed in the U.S. Pharmacopeia orother generally recognized pharmacopeia for use in animals, and moreparticularly in humans.

The term “carrier” includes a diluent, adjuvant (e.g., Freund's adjuvant(complete and incomplete)), excipient, or vehicle with which thetherapeutic is administered. Such pharmaceutical carriers can be sterileliquids, such as water and oils, including those of petroleum, animal,vegetable or synthetic origin, such as peanut oil, soybean oil, mineraloil, sesame oil and the like. Examples of suitable pharmaceuticalcarriers are described in “Remington's Pharmaceutical Sciences” by E. W.Martin.

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well-known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsinclude starch, glucose, lactose, sucrose, gelatin, malt, rice, flour,chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a subjectand the specific active ingredients in the dosage form. The compositionor single unit dosage form, if desired, can also contain minor amountsof wetting or emulsifying agents, or pH buffering agents.

Typical dosage forms comprising a glycopyrronium tosylate compositionprovided herein, or a pharmaceutically acceptable solvate or hydratethereof, lie within the range of from about 50 mg to about 150 mg ofactive compound per day, given as a single once-a-day dose in themorning or as divided doses throughout the day. Particular dosage formscan have about 50, 55, 60, 65, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, 100, 101, 102, 103, 104, 105, 110, 115, 120, 125, 130, 135, 140,145, or 150 mg of the active compound.

Topical Dosage Forms

Also provided are topical dosage forms. Topical dosage forms include,but are not limited to, sprays, aerosols, creams, lotions, ointments,gels, solutions, emulsions, suspensions, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences,16^(th), 18^(th), 20^(th), and 22^(nd) eds., Mack Publishing, Easton Pa.(1980, 1990, 2000 & 2012); and Introduction to Pharmaceutical DosageForms, 4th ed., Lea & Febiger, Philadelphia (1985).

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical dosage forms encompassed herein arewell known to those skilled in the pharmaceutical arts, and depend onthe particular tissue to which a given pharmaceutical composition ordosage form will be applied. With that fact in mind, typical excipientsinclude, but are not limited to, water, acetone, ethanol, ethyleneglycol, propylene glycol, butane-1,3 diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to form lotions,tinctures, creams, emulsions, gels or ointments, which are nontoxic andpharmaceutically acceptable. Moisturizers or humectants can also beadded to pharmaceutical compositions and dosage forms if desired.Examples of such additional ingredients are well known in the art. See,e.g., Remington's Pharmaceutical Sciences, 16^(th), 18^(th), 20^(th),and 22^(nd) eds., Mack Publishing, Easton Pa. (1980, 1990, 2000 & 2012).

In an embodiment, provided herein is a topical dosage form comprisingabout 50-150 mg of active compound in an alcohol:water solution and witha pH buffering agent. In an embodiment, the active compound is about0.25-6% of the topical dosage form. In an embodiment, the topical dosageform comprises about 70-105 mg of active compound. In an embodiment, thetopical dosage form comprises about 70 mg of active compound. In anembodiment, the topical dosage form comprises about 105 mg of activecompound. In an embodiment, the alcohol:water ratio of the topicaldosage form is selected over the range of 50:50 to 70:30, preferablyover the range of 53:47 to 58:42. In an embodiment, the buffering agentis about 0.2 to 0.5% of the topical dosage form. In an embodiment, thebuffering agent of the topical dosage form is citric acid/sodiumcitrate. In an embodiment, the pH of the topical dosage form is selectedover the range of 4.0 to 5.0. In an embodiment, the pH of the topicaldosage form is about 4.5.

In an embodiment, the topical dosage form is provided in a wipe fortopical administration. In an embodiment, the topical dosage form isprovided in a wipe soaked with the topical dosage form. In anembodiment, the topical dosage form is provided in a wipe soaked withthe topical dosage form provided in a package comprising several wipesper package.

Dosage and Unit Dosage Forms

In human therapeutics, the doctor will determine the posology which heconsiders most appropriate according to a preventive or curativetreatment and according to the age, weight, stage of the disorder andother factors specific to the subject to be treated. Alternatively, theposology will be provided on or in packaging providing in anover-the-counter kit comprising a dosage form. In certain embodiments,doses are from about 50 mg to about 150 mg active compound per day foran adult. Particular dosage forms can have about 50, 55, 60, 65, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105,110, 115, 120, 125, 130, 135, 140, 145, or 150 mg of the activecompound.

In further aspects, provided are methods of treating or preventing adisorder of a subject by administering, to a subject in need thereof, aneffective amount of a glycopyrronium tosylate composition providedherein, or a pharmaceutically acceptable solvate or hydrate thereof. Theamount of the glycopyrronium tosylate composition which will beeffective in the prevention or treatment of a disorder or one or moresymptoms thereof will vary with the nature and severity of the diseaseor condition, and the route by which the active ingredient isadministered. The frequency and dosage will also vary according tofactors specific for each subject depending on the specific therapy(e.g., therapeutic or prophylactic agents) administered, the severity ofthe disorder, disease, or condition, the route of administration, aswell as age, body, weight, response, and the past medical history of thesubject. Effective doses may be extrapolated from dose-response curvesderived from in vitro or animal model test systems.

In certain embodiments, administration of the same composition may berepeated and the administrations may be separated by at least 1 day, 2days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75days, 3 months, 6 months, or more. In other embodiments, administrationof the same prophylactic or therapeutic agent may be repeated and theadministration may be separated by at least at least 1 day, 2 days, 3days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3months, 6 months, or more.

Kits

Also provided are kits for use in methods of treatment of a disordersuch as hyperhidrosis. The kits can include a compound or compositionprovided herein, a second agent or composition, and instructionsproviding information regarding usage for treating the disorder.Instructions may be provided in any form which can be convenientlyaccessed and/or received by a subject, including, but not limited to,printed form, floppy disc, CD, DVD, USB drive, website address,smartphone application, tablet application, wearable device application,text message, and message through a social media service.

In some embodiments, suitable packaging is provided. As used herein,“packaging” includes a material customarily used in a system and capableof holding within fixed limits a glycopyrronium tosylate compositionprovided herein and/or a second agent suitable for administration to asubject. Such materials include glass and plastic (e.g., polyethylene,polypropylene, and polycarbonate) bottles, vials, paper, plastic, wipes,and plastic-foil laminated envelopes and the like.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL (microliters); mM (millimolar); μM (micromolar); Hz(Hertz); MHz (megahertz); mmol (millimoles); hr or hrs (hours); min(minutes); MS (mass spectrometry); ESI (electrospray ionization); TLC(thin layer chromatography); HPLC (high pressure liquid chromatography);THF (tetrahydrofuran); CDCl₃ (deuterated chloroform); AcOH (aceticacid); DCM (dichloromethane); DMSO (dimethylsulfoxide); DMSO-d₆(deuterated dimethylsulfoxide); EtOAc (ethyl acetate); MeOH (methanol);and BOC (t-butyloxycarbonyl).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCelsius). All reactions are conducted at room temperature unlessotherwise noted. Synthetic methodologies illustrated herein are intendedto exemplify the applicable chemistry through the use of specificexamples and are not indicative of the scope of the disclosure.

Example 1 Preparation of Glycopyrronium Tosylate Using Methyl Tosylateas Methylation Agent Step 1: Preparation of Glycopyrrolate Base (Mixtureof Erythro/Threo Base)

Cyclopentylmandelic acid is activated by reaction under heating with1,1-carbonyldiimidazole in toluene. N-methyl-3-pyridinol is added andstirred for at least five hours. After in-process testing to confirmcompletion of reaction, the mixture is cooled, washed with water, andthe toluene solution concentrated to a mixture containing between 20-40%toluene and less than 4% residual cyclopentyl mandelic acid. Thismixture is used directly in the next step.

Step 2: Preparation of Glycopyrrolate Base threo Pair as5-Nitroisophthalate Salt

This step effectively resolves the mixture of threo and erythrodiastereomers of the free base intermediate to provide the threo pair atgreater than 96%. The process relies on the significantly differentsolubilities of the 5-nitroisophthalate salts of the threo and erythrodiastereomers of glycopyrrolate free base.

5-Nitroisophthalic acid (1 eq.) was dissolved in methanol (20 vol) atroom temperature with moderate agitation. The glycopyrrolate base (1eq.) obtained in Step 1 was then added. After crystallization wasinitiated, the mixture was stirred for an additional 4 hours at roomtemperature. The solids were then recovered in a filtration centrifugeand washed with methanol.

The crude product was then suspended in approximately 6 volumes ofmethanol. The suspension was stirred at approximately 65° C. for onehour, then cooled to 20° C. and stirred for an additional 4 hours. Theproduct was again recovered in a filtration centrifuge, washed withmethanol, spun dry at 1290 RPM for 15 minutes, and then discharged aswet glycopyrrolate 5-nitroisophthalate. The product was tested foridentification, loss on drying, and melting point. The ratio ofthreo:erythro diastereomeric pairs was typically 96:4.

Step 3: Preparation of threo-Glycopyrrolate Base

The threo-glycopyrrolate base was obtained by treatment of the wet5-nitroisophthalate salt obtained in Step 2 with aqueous sodiumhydroxide and toluene. A biphasic mixture was obtained in which thedisodium salt of 5-nitroisophthalic acid resided in the aqueous layerand the threo-glycopyrrolate base was contained in the toluene layer.

The wet 5-nitroisophthalate salt of threo-glycopyrrolate base wasdissolved in approximately 8 volumes of purified water at roomtemperature. Toluene (approximately 3 volumes) was added. Withagitation, a slight excess of 30% aqueous sodium hydroxide was added andthe mixture stirred for 15 minutes. A sample of the biphasic mixture wasthen taken and the pH of the aqueous layer verified to be in the range11.5 to 12.5. In some instances, the pH was adjusted by addition ofadditional aqueous sodium hydroxide. The lower aqueous layer was removedby decanting and the upper toluene layer washed three times withpurified water. The toluene was then removed by distillation underreduced pressure to yield the free base as an oil which was useddirectly in the next step.

Step 4: Preparation of Crude Glycopyrronium Tosylate

The threo-glycopyrrolate base obtained in the previous step wasdissolved in four volumes of acetone and treated with 1.1 eq. ofmethyl-p-toluenesulfonate. The mixture was stirred for a minimum ofthree hours at room temperature, typically for about 12 hours at roomtemperature. Completion of the reaction was monitored by TLC until theremaining free base was not more than about 2%. The crude glycopyrroniumtosylate was recovered using a filtration centrifuge and washed twicewith a minimum of acetone. The wet cake obtained was dried under vacuumat 50° C. until the loss on drying was not more than 2.0%.

Step 5: Purification and Isolation of threo-Glycopyrronium Tosylate

The purpose of the following purification steps was to reduce thecontent of the erythro isomer to the release limit of not more than0.4%.

In the first purification step, the dried crude glycopyrronium tosylatewas triturated in three volumes of purified water for five hours. Theproduct was recovered using a filtration centrifuge and washed with 1volume of cold (<10° C.) purified water. The wet cake was then dissolvedin four volumes of purified water at 60° C. with agitation. The solutionobtained was cooled to 35° C. and held until crystallization began(typically about 1 hour). The mixture was then cooled to 20° C. andagitated for a further 5 hours. The product was then recovered using afiltration centrifuge and washed with 1 volume of cold (<10° C.)purified water. Finally, the product was recrystallized a second time ina similar fashion from 3 volumes of purified water with polishfiltration of the 60° C. solution prior to cooling.

At each step of the purification process, the wet cake was sampled andanalyzed for loss on drying and erythro isomer content. The erythroisomer limit of 0.4% was typically met after the second crystallization,however additional recrystallization steps were performed as requireduntil the erythro isomer limit was met. The product was tray dried atnot more than 40° C. without vacuum for a minimum of 8 hours until thewater content met the release criteria of 2.5%-4.0%.

Elemental analysis: C, 61.59%; H, 7.27%; N, 2.80%; S, 6.31%. Themolecular formula of glycopyrronium tosylate monohydrate is C₂₆H₃₇NO₇S,which corresponds to: C, 61.51%; H, 7.35%; N, 2.76%; and S, 6.32%.

¹H NMR (DMSO-d₆): δ=1.15 (m, 1H), 1.20 (m, 1H), 1.40 (m, 1H), 1.50 (m,2H), 1.60 (m, 3H), 2.05 (m, 1H), 2.30 (s, 3H), 2.65 (m, 1H), 2.90 (m,1H), 3.05 (s, 3H), 3.15 (s, 3H), 3.50 (m, 1H), 3.60 (d, 1H), 3.70 (m,1H), 3.80 (dd, 1H), 5.37 (m, 1H), 5.82 (s, 1H), 7.10 (d, 2H), 7.27 (t,1H), 7.35 (7.47 (d, 2H), 7.59 (d, 2H).

ESI-MS(+): m/z 318 (glycopyrronium); ESI-MS(−): m/z 171 (tosylate).

IR (ATR): 681-907 cm-1 (C—H arom.); 1012, 1036 cm⁻¹ (C—N, C—O, C═S str);1195 cm⁻¹ (C—O ester str); 1320, 1361, 1445 cm⁻¹ (S═O); 1734 cm⁻¹ (C═Oester); 2868-3033 cm⁻¹ (C—H aliph); 3419, 3569 cm⁻¹ (O—H str).

Impurity Profile

The measured impurities were consistent with those of the United StatesPharmacopeia monograph of Glycopyrrolate, the bromide salt. They are:Impurity A (5-nitroisophthalic acid), believed to be from the chiralresolution of the glycopyrrolate base intermediate; Impurity B(glycopyrrolate base intermediate); and Impurity C (cyclopentylmandelicacid) which is used in the first step of the synthesis, and is alsobelieved to be the primary degradation product. No other impurities wereobserved in the batches or forced degradation studies. All batches havecontained very low levels of total impurities and easily met the limitof 0.15%.

An additional potential impurity is methyl tosylate used in thequaternization step. Methyl tosylate is believed to be unstable inaqueous medium and effectively cleared by the final crystallizationsteps. Methyl tosylate levels are consistently not detected, at a limitof detection of 2.25 ppm.

All publications, patents, and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication, patent, or patent application were specifically andindividually indicated to be incorporated by reference. While theclaimed subject matter has been described in terms of variousembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the claimed subject matter is limited solely by the scope ofthe following claims, including equivalents thereof.

1.-30. (canceled)
 31. A glycopyrronium tosylate composition produced bya method comprising: purifying glycopyrronium tosylate by one or morecrystallizations in an aqueous solvent to obtain a purifiedglycopyrronium tosylate, wherein the aqueous solvent consistsessentially of water; the composition comprises threo-glycopyrroniumtosylate and erythro-glycopyrronium tosylate, wherein thethreo-glycopyrronium tosylate is at least 98% of the totalglycopyrronium tosylate content of the composition and theerythro-glycopyrronium tosylate is less than 2% of the totalglycopyrronium tosylate content of the composition.
 32. Theglycopyrronium tosylate composition of claim 31, wherein thethreo-glycopyrronium tosylate is at least 99% of the totalglycopyrronium tosylate content of the composition and theerythro-glycopyrronium tosylate is less than 1% of the totalglycopyrronium tosylate content of the composition.
 33. Theglycopyrronium tosylate composition of claim 31, wherein thethreo-glycopyrronium tosylate is at least 99.5% of the totalglycopyrronium tosylate content of the composition and theerythro-glycopyrronium tosylate is less than 0.5% of the totalglycopyrronium tosylate content of the composition.
 34. Theglycopyrronium tosylate composition of claim 31, wherein thethreo-glycopyrronium tosylate is at least 99.6% of the totalglycopyrronium tosylate content of the composition and theerythro-glycopyrronium tosylate is less than 0.4% of the totalglycopyrronium tosylate content of the composition.
 35. A glycopyrroniumtosylate composition comprising threo-glycopyrronium tosylate anderythro-glycopyrronium tosylate, wherein the threo-glycopyrroniumtosylate is at least 98% of the total glycopyrronium tosylate content ofthe composition and the erythro-glycopyrronium tosylate is less than 2%of the total glycopyrronium tosylate content of the composition.
 36. Theglycopyrronium tosylate composition of claim 35, wherein thethreo-glycopyrronium tosylate is at least 99% of the totalglycopyrronium tosylate content of the composition and theerythro-glycopyrronium tosylate is less than 1% of the totalglycopyrronium tosylate content of the composition.
 37. Theglycopyrronium tosylate composition of claim 35, wherein thethreo-glycopyrronium tosylate is at least 99.5% of the totalglycopyrronium tosylate content of the composition and theerythro-glycopyrronium tosylate is less than 0.5% of the totalglycopyrronium tosylate content of the composition.
 38. Theglycopyrronium tosylate composition of claim 35, wherein thethreo-glycopyrronium tosylate is at least 99.6% of the totalglycopyrronium tosylate content of the composition and theerythro-glycopyrronium tosylate is less than 0.4% of the totalglycopyrronium tosylate content of the composition.
 39. Theglycopyrronium tosylate composition of claim 31, wherein the aqueoussolvent consists of water.
 40. The glycopyrronium tosylate compositionof claim 31, wherein in the method the glycopyrronium tosylate ispurified by at least two crystallizations in the aqueous solvent. 41.The glycopyrronium tosylate composition of claim 31, wherein the methodfurther comprising producing glycopyrronium tosylate by contactingglycopyrrolate base with methyl tosylate to produce glycopyrroniumtosylate:

wherein the glycopyrrolate base is contacted with a water-miscibleorganic solvent.
 42. The glycopyrronium tosylate composition of claim41, wherein the water-miscible organic solvent is a water-misciblealdehyde, organic acid, ketone, nitrile, diol, alcohol, aminoalcohol,glycol, sulfoxide, ether, cyclic ether, cyclic diether, amine, polyol,or cyclic amine comprising from 1 to 6 carbon atoms.
 43. Theglycopyrronium tosylate composition of claim 41, wherein thewater-miscible organic solvent is acetone.
 44. The glycopyrroniumtosylate composition of claim 41, wherein the reaction is conducted at atemperature selected over the range of 20° C. to 26° C.
 45. Theglycopyrronium tosylate composition of claim 41, wherein theglycopyrronium tosylate is produced as a mixture of threo-glycopyrroniumtosylate and erythro-glycopyrronium tosylate, and thethreo-glycopyrronium tosylate is at least 95% of the totalglycopyrronium tosylate in the mixture and the erythro-glycopyrroniumtosylate is less than 5% of the total glycopyrronium tosylate in themixture.
 46. The glycopyrronium tosylate composition of claim 45,wherein the threo-glycopyrronium tosylate is at least 96% of the totalglycopyrronium tosylate in the mixture and the erythro-glycopyrroniumtosylate is less than 4% of the total glycopyrronium tosylate in themixture.
 47. The glycopyrronium tosylate composition of claim 45,wherein the threo-glycopyrronium tosylate is at least 97% of the totalglycopyrronium tosylate in the mixture and erythro-glycopyrroniumtosylate is less than 3% of the total glycopyrronium tosylate in themixture.
 48. The glycopyrronium tosylate composition of claim 41,wherein the method further comprising producing glycopyrrolate base bycontacting a glycopyrrolate base, 5-nitroisophthalate salt with aninorganic base to form the glycopyrrolate base:


49. The glycopyrronium tosylate composition of claim 48, wherein theinorganic base is aqueous sodium hydroxide.
 50. The glycopyrroniumtosylate composition of claim 48, wherein the glycopyrrolate base,5-nitroisophthalate salt, and inorganic base are contacted with awater-immiscible organic solvent.
 51. The glycopyrronium tosylatecomposition of claim 50, wherein the water-immiscible organic solvent isselected from the group consisting of benzene, n-butanol, carbontetrachloride, chloroform, cyclohexane, ethylene chloride, heptane,hexane, pentane, toluene, trichloroethylene, and xylene.
 52. Theglycopyrronium tosylate composition of claim 50, wherein thewater-immiscible organic solvent is toluene.
 53. The glycopyrroniumtosylate composition of claim 48, wherein the glycopyrrolate base isproduced as a mixture of threo-glycopyrrolate base anderythro-glycopyrrolate base, and the threo-glycopyrrolate base is atleast 95% of the total glycopyrrolate base produced and theerythro-glycopyrrolate base is less than 5% of the total glycopyrrolatebase produced.
 54. The glycopyrronium tosylate composition of claim 53,wherein the threo-glycopyrrolate base is at least 96% of the totalglycopyrrolate base produced and the erythro-glycopyrrolate base is lessthan 4% of the total glycopyrrolate base produced.
 55. Theglycopyrronium tosylate composition of claim 53, wherein thethreo-glycopyrrolate base is at least 97% of the total glycopyrrolatebase produced and the erythro-glycopyrrolate base is less than 3% of thetotal glycopyrrolate base produced.
 56. The glycopyrronium tosylatecomposition of claim 48, wherein the method further comprising producingglycopyrrolate base, 5-nitroisophthalate salt by contacting aglycopyrrolate base with 5-nitroisophthalic acid to form theglycopyrrolate base, 5-nitroisophthalate salt:


57. The glycopyrronium tosylate composition of claim 56, wherein theglycopyrrolate base and 5-nitroisophthalic acid are contacted withmethanol.
 58. The glycopyrronium tosylate composition of claim 56,wherein the contacting of a glycopyrrolate base with 5-nitroisophthalicacid is conducted at a temperature selected over the range of 20° C. to26° C.
 59. The glycopyrronium tosylate composition of claim 56, whereinthe method further comprising producing glycopyrrolate base bycontacting cyclopentylmandelic acid with 1-methylpyrrolidin-3-ol to formthe glycopyrrolate base:


60. A glycopyrronium tosylate composition produced by a methodcomprising: (i) contacting cyclopentylmandelic acid with1-methylpyrrolidin-3-ol to form glycopyrrolate base:

(ii) contacting the glycopyrrolate base with 5-nitroisophthalic acid toform glycopyrrolate base, 5-nitroisophthalate salt:

(iii) contacting the glycopyrrolate base, 5-nitroisophthalate salt withan inorganic base to form glycopyrrolate base:

(iv) contacting the glycopyrrolate base with methyl tosylate to produceglycopyrronium tosylate:

wherein the glycopyrrolate base is contacted with a water-miscibleorganic solvent; and (v) purifying the glycopyrronium tosylate obtainedin step (iv) by one or more crystallizations in an aqueous solvent toobtain a purified glycopyrronium tosylate; wherein the aqueous solventconsists essentially of water.
 61. The glycopyrronium tosylatecomposition of claim 60, wherein the purified glycopyrronium tosylate ofstep (v) is a mixture of threo-glycopyrronium tosylate anderythro-glycopyrronium tosylate, and the threo-glycopyrronium tosylateis at least 99% of the total glycopyrronium tosylate in the mixture andthe erythro-glycopyrronium tosylate is less than 1% of the totalglycopyrronium tosylate in the mixture.
 62. The glycopyrronium tosylatecomposition of claim 61, wherein the threo-glycopyrronium tosylate is atleast 99.5% of the total glycopyrronium tosylate in the mixture and theerythro-glycopyrronium tosylate is less than 0.5% of the totalglycopyrronium tosylate in the mixture.
 63. The glycopyrronium tosylatecomposition of claim 61, wherein the threo-glycopyrronium tosylate is atleast 99.6% of the total glycopyrronium tosylate in the mixture and theerythro-glycopyrronium tosylate is less than 0.4% of the totalglycopyrronium tosylate in the mixture.
 64. The glycopyrronium tosylatecomposition of claim 60, wherein the step (v) is purifying theglycopyrronium tosylate obtained in step (iv) by at least twocrystallizations in the aqueous solvent.
 65. The glycopyrronium tosylatecomposition of claim 60, wherein in step (v) the aqueous solventconsists of water.
 66. The glycopyrronium tosylate composition of claim60, wherein in step (iv) the water-miscible organic solvent is acetone.67. The glycopyrronium tosylate composition of claim 60, wherein in step(iii) the glycopyrrolate base, 5-nitroisophthalate salt is dissolved inwater and contacted with toluene, and the inorganic base is aqueoussodium hydroxide.
 68. The glycopyrronium tosylate composition of claim60, wherein in step (ii) the glycopyrrolate base is contacted with5-nitroisophthalic acid in methanol.